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TitleRational design of flavivirus E protein vaccine optimizes immunogenicity and mitigates antibody dependent enhancement risk.
Journal, issue, pagesNat Commun, Vol. 16, Issue 1, Page 11558, Year 2025
Publish dateDec 22, 2025
AuthorsYimeng Wang / Andrey Galkin / Xiaoran Shang / Alexander Marin / Shaohua Jin / Ting-Juan Ye / Shridhar Bale / Chi-I Chiang / Ananda Chowdhury / Agnes L Chenine / Ashley Turonis / Jack Greenhouse / Rebecca Stone / Jaclyn Wear / Swagata Kar / Hanne Andersen / Yan-Jang S Huang / Dana L Vanlandingham / Stephen Higgs / Rena G Lapidus / Thomas Fuerst / David J Weber / Richard T Wyatt / Christel Iffland / Theodore C Pierson / Alexander K Andrianov / Edwin Pozharski / Yuxing Li /
PubMed AbstractFlaviviruses are a family of related viruses that cause substantial global morbidity and mortality. Vaccination against one flavivirus can sometimes exacerbate disease caused by related viruses ...Flaviviruses are a family of related viruses that cause substantial global morbidity and mortality. Vaccination against one flavivirus can sometimes exacerbate disease caused by related viruses through antibody-dependent enhancement (ADE) or interfere with the efficacy of subsequent vaccines. To address this challenge, we develop a vaccine strategy by introducing G5C/G102C mutations into the flavivirus envelope (E) glycoprotein. These mutations promote E dimerization through the formation of an inter-chain disulfide bond that conceals the immunodominant and ADE-prone fusion loop epitope (FLE). We validate this design on E proteins from multiple flaviviruses through biochemical, antigenic, and structural analyses. The resulting vaccine candidate, CC_FLE sE, derived from the Zika virus (ZIKV) and formulated with an advanced supramolecular adjuvant, provides significant protection in female mice challenged with ZIKV and prevents ADE caused by a related flavivirus, Dengue virus. In genetically modified mice expressing diverse human immunoglobulin loci, ZIKV CC_FLE sE induces robust neutralizing antibody responses targeting key ZIKV E protein epitopes, including the E-dimer-dependent epitope (EDE), indicating that ZIKV CC_FLE sE can elicit protective antibody responses within the human naïve B cell repertoire. Therefore, CC_FLE sE represents a promising strategy for developing flavivirus vaccines that minimize ADE risk while maintaining high protective efficacy.
External linksNat Commun / PubMed:41429771 / PubMed Central
MethodsEM (single particle)
Resolution3.45 - 7.96 Å
Structure data

70338

9od2

EMDB-70338, PDB-9od2:
Cryo-EM structure of modified Zika virus E protein dimer complexed with a neutralizing antibody SMZAb2 Fab
Method: EM (single particle) / Resolution: 4.09 Å

71715

9pl9

EMDB-71715, PDB-9pl9:
Cryo-EM structure of modified JEV virus E protein dimer
Method: EM (single particle) / Resolution: 4.18 Å

EMDB-71727: West Nile virus E protein
Method: EM (single particle) / Resolution: 7.96 Å

71728

9pm6

EMDB-71728, PDB-9pm6:
Cryo-EM structure of modified Zika virus E protein dimer complexed with a neutralizing antibody OZ-D4 Fab
Method: EM (single particle) / Resolution: 3.45 Å

Source
  • zika virus
  • homo sapiens (human)
  • japanese encephalitis virus
  • West Nile virus
KeywordsVIRAL PROTEIN/IMMUNE SYSTEM / neutralizing antibody / VIRAL PROTEIN / VIRAL PROTEIN-Immune System complex

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